The goal of this clinical trial is to learn if a metformin dose of 1500 mg or 2250 mg per day is better to treat polycystic ovary syndrome (PCOS) in adults. It will also learn about the adverse effects of metformin. The trial aims to evaluate which metformin dose is better for: 1. improving biochemical and clinical outcomes 2. gastrointestinal side-effects 3. mental health and quality of life Participants will: * Be randomized to take metformin at a dose of either 1500mg or 2250mg every day for 6 months * Visit the clinic three times during the trial for checkups and tests * Answer questionnaires on menstrual cyclicity, mental health, quality of life and side-effects
INTRODUCTION Polycystic ovary syndrome (PCOS) remains a key public health burden as it is one of the most common endocrine and metabolic disorders affecting up to 13% of women globally. The Rotterdam diagnostic criteria were updated and internationally endorsed in the 2023 International PCOS guideline and include a) ovulatory and menstrual dysfunction, b) biochemical and/or clinical hyperandrogenism and c) polycystic ovary morphology (PCOM) at ultra-sound. For a diagnosis in adults two of three criteria are required, with PCOM remaining nonspecific for PCOS in adolescents. Women with PCOS present with diverse features; metabolic (weight gain, obesity, insulin resistance and diabetes) reproductive (infertility and pregnancy complications), endocrine (hyperandrogenism, hirsutism and acne) and psychosocial (depression, anxiety and poor quality of life). While lifestyle management is strongly recommended for weight management, for those with higher body mass index (BMI), sustainable efficacy for weight loss can be limited and additional pharmacological treatment may be needed. The 2023 Updated International PCOS Guideline recommends that metformin, in addition to lifestyle, should be considered in adults with PCOS and BMI ≥ 25 kg/m2 for prevention of weight gain and management of weight and metabolic disorders. Metformin may be considered in adults with BMI \< 25 kg/m2 and adolescents with PCOS, acknowledging more limited evidence. The aim of this randomized controlled trial (RCT) is to evaluate whether a metformin dose of 1500 mg is inferior compared to a dose of 2250 mg per day for females 18-37 years of age with PCOS in: 1. improving biochemical and clinical outcomes 2. gastrointestinal side-effects 3. mental health and quality of life MATERIALS AND METHODS A double-blind, randomized controlled trial, including adults (age 18-37 years) with PCOS and a BMI ≥ 25 kg/m2 will be carried out. The randomization will be computer-generated and performed by the hospital pharmacy with 1:1 allocation in random blocks. Power analysis has indicated that a total number of 184 females (92 in each group) will be needed to reveal a 4 kg weight reduction (equals 5% weight reduction for a person weighting 80 kg) with an 80% power. We estimated a 15% drop-out in our power analysis. Potential participants for the study will be recruited from females referred to the Reproductive Medicine Unit at Helsinki University Hospital and by advertising via the patient organization for those with PCOS (Korento). The internationally indorsed Rotterdam criteria will be used to diagnose women with PCOS. Pregnant women, women breastfeeding, women with untreated thyroid disease, hyperprolactinemia, other conditions with hyperandrogenism or use of hormonal contraceptive during the last three months will be excluded. Women willing to participate in the study will be randomized to metformin 1500mg or 2250 mg per day for a 6-month period. Blood samples (on hyperandrogenism and metabolism), clinical examination (anthropometry and hirsutism) and a questionnaire (menstrual cyclicity, mental health, quality of life, side-effects) will be performed before starting the metformin medication, as well as at 3 and 6 months after onset of medication. Polycystic ovary morphology will be evaluated by measuring anti-mullerian hormone levels (AMH) and by vaginal ultrasound.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
184
metformin 500mg tablets, 3 times per day
Metformin 750mg, 3 times daily
The Reproductive Medicine Unit, Helsinki University Hospital
Helsinki, Finland
Weight
Weight will be measured by a standard scale to an accuracy of +/- 0,1kg.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Homeostatic model assessment for insulin resistance (HOMA-IR)
HOMA-IR will be calculated with the formula: fasting plasma glucose (mmol/L) × fasting serum insulin (mU/L) divided by 22.5 (9)
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Hirsutism
Modified Ferriman Gallwey score (mFG) will be measured and a score of 4 or more will be regarded as hirsutism in Caucasian women, whereas a score of 6 or more will be regarded hirsutism for other ethnicities
Time frame: The investigators will report change from baseline to 14 and 26 weeks.
Total testosterone
Testosterone nmol/l (liquid chromatography with tandem mass spectrometry (LC-MS/MS). All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Appearance of severe of adverse effects
In our questionnaire the investigators will ask the participants whether they have experienced abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks and grade the symptoms from 1-5 (1 being never and 5 being all the time). The investigators will count the scores and give each participant a score between 5-25. A severe adverse effect is defined as a score of 4 or more in one of the questions (indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks).
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Anti-Mullerian hormone (AMH)
AMH will be measured in ug/l. All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Body mass index (BMI)
Weight (kilogram) and height (metre) will be combined to report BMI in kg/m\^2
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Waist circumference (WC)
WC will be measured halfway between the participant's lowest rib and the top of the participant's hipbone
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Waist-hip-ratio (WHR)
WHR will be calculated as waist measurement divided by hip measurement (W⁄H). Hip circumference is determined as the maximum value over the glottal region, measured to the nearest centimetre.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Body adiposity index (BAI)
BAI will be measured using the following equation: hip circumference (cm)/height (m) - 18
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Body composition
Body composition will be measured with a multi-frequency segmental body composition analyzer (TANITA Health Ware) WHR (Waist-hip-ratio). Will be calculated as waist measurement divided by hip measurement (W⁄H). Hip circumference is determined as the maximum value over the glottal region, measured to the nearest centimetre. WC (Waist circumference). Measured halfway between the participant's lowest rib and the top of the participant's hipbone BAI (Body adiposity index). Will be measured using the following equation: hip circumference (cm)/height (m) - 18 BP (blood pressure) (systolic and diastolic) and pulse. Will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Blood pressure (BP)
BP (systolic and diastolic) will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position
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Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Pulse
Pulse will be measured twice with at least 3 minutes apart after at least 10 min rest from non-dominant upper extremity in a subject in supine position
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Fasting glucose
fasting glucose mmol/l (photometric hexokinase method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Fasting insulin
fasting insulin mU/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
HbA1C
HbA1C mmol/mol (photometric enzymatic method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Lipids (cholesterol and its subclasses, triglycerides)
Total cholesterol, mmol/l and triglycerides mmol/l with an enzymatic photometric method, LDL and HDL mmol/l with a direct enzymatic photometric method All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
C-reactive protein (CRP)
CRP will be measured in mg/l (photometric immunochemical method) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
2-hour oral glucose tolerance test (OGTT)
2-hour OGTT mmol/l
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Alanine Aminotransferase (ALAT)
ALAT will be measured in U/l (photometric method according to the International Federation of Clinical Chemistry and Laboratory Medicine recommendation) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Gamma-glutamyl transferase (G-GT)
G-GT will be measured in U/l (photometric method according to the International Federation of Clinical Chemistry and Laboratory Medicine recommendation) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Fatty Liver Index (FLI)
FLI will be measured by the following formula: FLI = (e\^y) / (1 + e\^y) \* 100 where: y = 0.953 \* ln(TG) + 0.139 \* BMI + 0.718 \* ln(GGT) + 0.053 \* WC - 15.745 e is the base of the natural logarithm (approximately 2.718) ln denotes the natural logarithm TG is triglycerides in mg/dL BMI is body mass index in kg/m² GGT is gamma-glutamyltransferase in U/L WC is waist circumference in cm All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Matsuda Index
Matsuda Index will be measured by the following formula: Matsuda Index = 10,000 / √\[(fasting glucose (mg/dL) \* fasting insulin (µU/mL)) \* (mean glucose (mg/dL) \* mean insulin (µU/mL) during OGTT) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Triglyceride-Glucose (TyG) index
TyG Index will be measured by the following formula: TyG Index=fasting triglycerides (mg/dL) \* fasting glucose (mg/dL) / 2 All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change in outcomes from baseline to 14 and 26 weeks
Acne
The investigators will use the PCOS-Q to ask about acne (score 1-7)
Time frame: The investigators will report change from baseline to 14 and 26 weeks
Alopecia
The investigators will use the PCOS-Q to ask about alopecia (score 1-7)
Time frame: The investigators will report change from baseline to 14 and 26 weeks
Free androgen index (FAI)
FAI will be calculated with the following formula: FAI = 100 X ((Total Testosterone (nmol/L)/SHBG (nmol/L)) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Sex hormone binding globulin (SHBG)
SHBG will be measured in nmol/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Dehydroepiandrosterone sulfate (DHEAS)
DHEAS will be measured in nmol/l (immunochemiluminometric assay) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Androstenedione
Androstenedione will be measured in nmol/l (liquid chromatography with tandem mass spectrometry (LC-MS/MS) All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Free testosterone
Free calculated testosterone will be measured in pmol/l (by Anderson Formula). All laboratory tests will be taken in the morning, between 7-10 am, after 12 hours fasting.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Menstrual regularity
Questionnaire, where asking if the menstrual cycle is regular (defined as 21 days or more but under 36 days)
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Menstrual cycle length
Questionnaire, where asking how long the two previous cycles were (days)
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Appearance of gastrointestinal adverse effects (GI AE)
In our questionnaire the investigators will ask the participants whether they have experienced abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks and grade the symptoms from 1-5 (1 being never and 5 being all the time). The investigators will count the scores and give each participant a score between 5-25. A severe adverse effect is defined as a score of 4 or more in one of the questions (indicating a daily experience of abdominal pain, reflux, nausea, diarrhoea or loss of appetite during the last two weeks).
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Quality of life (QoL)
The PCOS-Q is a questionnaire that was specifically designed to measure quality of life for women with PCOS. Questions on depression, anxiety, fear etc will be given scores from 1-7, depending on severity.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Weight stigma
In the questionnaire appearance of weight stigma and examples on it will be asked.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks
Follicle number per ovary (FNPO) and antral follicle count (AFC)
Vaginal ultrasound where the investigators measure FNPO and AFC will be performed at any stage of the cycle.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks.
Ovarian volume
Vaginal ultrasound where the investigators measure ovarian volume will be performed at any stage of the cycle.
Time frame: The investigators will measure change from baseline to 14 and 26 weeks.